Steroid hormone receptors including androgen receptor (AR), glucocorticoid receptor (GR), and the progesterone receptor (PR) require the ordered assembly of various chaperone and cochaperone proteins in order to reach a functional state. The final stage in the receptor maturation process requires the formation of a multimeric complex consisting of an Hsp90 dimer, p23, and one of several large immunophilins. Previously studies demonstrated that the large immunophilin, FK506-binding protein 52 (FKBP52), acts to potentiate GR, AR, and PR receptor signaling pathways, and FKBP52-mediated regulation of receptor function appears to be localized to the receptor hormone binding domain. In cellular studies, FKBP52 has been shown to preferentially regulate GR, AR, and PR receptor-mediated signal transduction. See, for example, Cheung-Flynn, J., et al., Mol. Endocrinol., 19:1654-66 (2005); Riggs, D. L., et al., EMBO J., 22:1158-67 (2003); and Tranguch, S., et al., J. Clin. Invest., 117:1824-34 (2007). Given its receptor specificity, FKBP52 represents an attractive therapeutic target for the treatment of hormone-dependent diseases.
It has been shown that when certain molecules bind to a previously described surface region on the AR hormone binding domain called BF3, they can generally inhibit AR function in the 100 μM range. See, Estebanez-Perpina, E., et al., Proc. Natl. Acad. Sci. USA, 104:16074-9 (2007).
To date, the only known compounds for inhibition of AR function are related to selective AR modulators that bind to the hormone binding pocket, and are therefore competitive inhibitors of endogenous hormone binding. However, there still exists a need for compounds which are selective AR modulators which are not competitive agonists or antagonists to endogenous hormone binding.